rs201198770

chr3-52369845-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_015512.5(DNAH1):c.5964G>A(p.Glu1988=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000627 in 1,610,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (0 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.29

Genes affected

DNAH1 (HGNC:2940): (dynein axonemal heavy chain 1) This gene encodes an inner dynein arm heavy chain that provides structural support between the radial spokes and the outer doublet of the sperm tail. Naturally occurring mutations in this gene are associated with primary ciliary dyskinesia and multiple morphological anomalies of the flagella that result in asthenozoospermia and male infertility. Mice with a homozygous knockout of the orthologous gene are viable but have reduced sperm motility and are infertile. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 3-52369845-G-A is Benign according to our data. Variant chr3-52369845-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 478470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.29 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.5964G>A	p.Glu1988=	synonymous_variant	38/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.6033G>A	p.Glu2011=	synonymous_variant	40/80
DNAH1	XM_017006130.2	c.5964G>A	p.Glu1988=	synonymous_variant	39/79
DNAH1	XM_017006131.2	c.6033G>A	p.Glu2011=	synonymous_variant	40/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.5964G>A	p.Glu1988=	synonymous_variant	38/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.6225G>A		non_coding_transcript_exon_variant	38/77	2

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000896 AC: 222 AN: 247816 Hom.: 0 AF XY: 0.000856 AC XY: 115 AN XY: 134414

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00140

Gnomad ASJ exome AF: 0.00331

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000295

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.000632 AC: 921 AN: 1457684 Hom.: 0 Cov.: 31 AF XY: 0.000623 AC XY: 451 AN XY: 724396

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00284

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000624

Gnomad4 OTH exome AF: 0.000881

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000550 AC XY: 41 AN XY: 74498

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.000703

EpiCase AF: 0.00169

EpiControl AF: 0.00166

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

DNAH1: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	8.8
Dann	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201198770; hg19: chr3-52403861;